Limits...
Bone Regulates Glucose Metabolism as an Endocrine Organ through Osteocalcin.

Shao J, Wang Z, Yang T, Ying H, Zhang Y, Liu S - Int J Endocrinol (2015)

Bottom Line: Skeleton was considered as a dynamic connective tissue, which was essential for mobility, calcium homeostasis, and hematopoietic niche.However more and more evidences indicate that skeleton works not only as a structural scaffold but also as an endocrine organ, which regulates several metabolic processes.In summary, skeleton has endocrine function via OCN and plays an important role in energy metabolism, especially in glucose metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedics, Shanghai Pudong New Area Gongli Hospital/Clinical School, The Second Military Medical University, Shanghai 200135, China.

ABSTRACT
Skeleton was considered as a dynamic connective tissue, which was essential for mobility, calcium homeostasis, and hematopoietic niche. However more and more evidences indicate that skeleton works not only as a structural scaffold but also as an endocrine organ, which regulates several metabolic processes. Besides osteoprotegerin (OPG), sclerostin (SOST), and Dickopf (DKK) which play essential roles in bone formation, modelling, remodelling, and homeostasis, bone can also secret hormones, such as osteocalcin (OCN), which promotes proliferation of β cells, insulin secretion, and insulin sensitivity. Additionally OCN can also regulate the fat cells and male gonad endocrine activity and be regulated by insulin and the neural system. In summary, skeleton has endocrine function via OCN and plays an important role in energy metabolism, especially in glucose metabolism.

No MeSH data available.


Related in: MedlinePlus

Proposed regulation of Esp expression and OCN carboxylation in mice. FoxO1 and ATF4 could bind to the promoter site to stimulate the transcription of Esp. The product of Esp is OST-PTP, which can suppress the carboxylation of prepro-OCN and in turn suppress the activity of OCN. VK, Vitamin K; SNS, sympathetic nervous system; OCN, osteocalcin; ucOCN, uncarboxylated osteocalcin.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4383405&req=5

fig4: Proposed regulation of Esp expression and OCN carboxylation in mice. FoxO1 and ATF4 could bind to the promoter site to stimulate the transcription of Esp. The product of Esp is OST-PTP, which can suppress the carboxylation of prepro-OCN and in turn suppress the activity of OCN. VK, Vitamin K; SNS, sympathetic nervous system; OCN, osteocalcin; ucOCN, uncarboxylated osteocalcin.

Mentions: In the recent years the molecular mechanism of Esp regulation was revealed (Figure 4). Two transcription factors, forkhead box protein O1 (FOXO1) and cyclic AMP-dependent transcription factor (ATF-4), are involved in the regulation of the total OCN [32]. FOXO1 is a conservative modulator of glucose metabolism in many organs, as well as insulin synthesis in β cells, and ATF4 regulates expression of many genes which mostly are important for adult bone formation and development [33, 34]. Osteoblast specific FoxO1 knocked out mice have low blood glucose level and high glucose tolerance [35], which is similar to the mice with high ucOCN level. This indicated that FoxO1 may be a modulator of Ocn transcription or posttranslational modification. Further studies on knocked out mice showed that FoxO1 could upregulate OST-PTP. Molecular experimental studies showed that FoxO1 could bind to a cognate FoxO1 binding site in the Esp promoter area and stimulate the expression of the downstream Esp; then OST-PTP would activate the carboxylation of OCN or ucOCN. The new formed cOCN would bind to hydroxyapatite and stay in bone matrix, and as a result the ucOCN would be downregulated [35]. These studies also found the binding site for ATF4 in the Esp promoter. Now it is not surprising that ATF4 can suppress obesity in mice and involve in the glucose homeostasis in human [36–38]. In fact even though ATF4 is mainly expressed in osteoblast, it functions quite similar to FoxO1. Via stimulating OST-PTP transcription ATF4 suppress the activity of OCN, in this way suppressing insulin secretion and insulin sensitivity [39, 40]. More details of OCN regulation are still unknown, and the endocrine regulation of OCN will be discussed in the later section of this review.


Bone Regulates Glucose Metabolism as an Endocrine Organ through Osteocalcin.

Shao J, Wang Z, Yang T, Ying H, Zhang Y, Liu S - Int J Endocrinol (2015)

Proposed regulation of Esp expression and OCN carboxylation in mice. FoxO1 and ATF4 could bind to the promoter site to stimulate the transcription of Esp. The product of Esp is OST-PTP, which can suppress the carboxylation of prepro-OCN and in turn suppress the activity of OCN. VK, Vitamin K; SNS, sympathetic nervous system; OCN, osteocalcin; ucOCN, uncarboxylated osteocalcin.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4383405&req=5

fig4: Proposed regulation of Esp expression and OCN carboxylation in mice. FoxO1 and ATF4 could bind to the promoter site to stimulate the transcription of Esp. The product of Esp is OST-PTP, which can suppress the carboxylation of prepro-OCN and in turn suppress the activity of OCN. VK, Vitamin K; SNS, sympathetic nervous system; OCN, osteocalcin; ucOCN, uncarboxylated osteocalcin.
Mentions: In the recent years the molecular mechanism of Esp regulation was revealed (Figure 4). Two transcription factors, forkhead box protein O1 (FOXO1) and cyclic AMP-dependent transcription factor (ATF-4), are involved in the regulation of the total OCN [32]. FOXO1 is a conservative modulator of glucose metabolism in many organs, as well as insulin synthesis in β cells, and ATF4 regulates expression of many genes which mostly are important for adult bone formation and development [33, 34]. Osteoblast specific FoxO1 knocked out mice have low blood glucose level and high glucose tolerance [35], which is similar to the mice with high ucOCN level. This indicated that FoxO1 may be a modulator of Ocn transcription or posttranslational modification. Further studies on knocked out mice showed that FoxO1 could upregulate OST-PTP. Molecular experimental studies showed that FoxO1 could bind to a cognate FoxO1 binding site in the Esp promoter area and stimulate the expression of the downstream Esp; then OST-PTP would activate the carboxylation of OCN or ucOCN. The new formed cOCN would bind to hydroxyapatite and stay in bone matrix, and as a result the ucOCN would be downregulated [35]. These studies also found the binding site for ATF4 in the Esp promoter. Now it is not surprising that ATF4 can suppress obesity in mice and involve in the glucose homeostasis in human [36–38]. In fact even though ATF4 is mainly expressed in osteoblast, it functions quite similar to FoxO1. Via stimulating OST-PTP transcription ATF4 suppress the activity of OCN, in this way suppressing insulin secretion and insulin sensitivity [39, 40]. More details of OCN regulation are still unknown, and the endocrine regulation of OCN will be discussed in the later section of this review.

Bottom Line: Skeleton was considered as a dynamic connective tissue, which was essential for mobility, calcium homeostasis, and hematopoietic niche.However more and more evidences indicate that skeleton works not only as a structural scaffold but also as an endocrine organ, which regulates several metabolic processes.In summary, skeleton has endocrine function via OCN and plays an important role in energy metabolism, especially in glucose metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedics, Shanghai Pudong New Area Gongli Hospital/Clinical School, The Second Military Medical University, Shanghai 200135, China.

ABSTRACT
Skeleton was considered as a dynamic connective tissue, which was essential for mobility, calcium homeostasis, and hematopoietic niche. However more and more evidences indicate that skeleton works not only as a structural scaffold but also as an endocrine organ, which regulates several metabolic processes. Besides osteoprotegerin (OPG), sclerostin (SOST), and Dickopf (DKK) which play essential roles in bone formation, modelling, remodelling, and homeostasis, bone can also secret hormones, such as osteocalcin (OCN), which promotes proliferation of β cells, insulin secretion, and insulin sensitivity. Additionally OCN can also regulate the fat cells and male gonad endocrine activity and be regulated by insulin and the neural system. In summary, skeleton has endocrine function via OCN and plays an important role in energy metabolism, especially in glucose metabolism.

No MeSH data available.


Related in: MedlinePlus